While diarrhea is typically considered a temporary nuisance in western countries, it is a significant cause of morbidity and mortality in the third world. In developing countries, diarrhea is the largest single cause of death among infants and children. Fluid and weight loss from diarrhea can result in severe dehydration, electrolyte imbalance, and acid-base disturbances. If left untreated, these imbalances can lead to death.
Oral rehydration solutions (ORS) are now routinely utilized throughout the world to correct the fluid and electrolyte losses associated with diarrhea. They have significantly decreased the mortality rate in third world children.
ORS contains at a minimum, water, glucose, and sodium. The principle underlying oral rehydration is the phenomenon of coupled transport. The presence of glucose in the ORS increases the absorption of sodium by the body. Every glucose molecule that crosses the intestinal epithelium brings a sodium ion with it, raising the concentration of ions in the blood stream and pulling water out of the gut. The exact concentration of glucose in the oral fluid is very important. Sodium absorption improves as the glucose concentration of the oral fluid is increased up to about 2.5% w/w. At higher concentrations, the glucose can no longer be efficiently absorbed leading to a net reduction in sodium and water absorption. In fact, higher concentrations of glucose increase the osmotic load in the gut, which pulls water out of the blood stream. This leads to a net loss of fluids and electrolytes further exacerbatin dehydration.
The World Health Organization recommends that an ORS contain 90 mEq of sodium per liter, 20 mEq of potassium per liter, 30 mEq carbonate per liter and 111 mM of glucose per liter. Other ORS's containing lower amounts of sodium have been demonstrated to be equally effective. For example, the American Academy of Pediatrics Committee on Nutrition recommendation for ORS is 40–60 mEq/L sodium, 20 mEq/L potassium, and 2.0–2.5 wt./wt. % carbohydrate.
Despite the reduction in mortality that has been associated with ORS, research continues regarding means to further ameliorate the incidence and/or duration of diarrhea. Part of this research has focused upon the role of zinc in diarrhea. Sazawal et al evaluated the impact of zinc supplementation in young children with diarrhea, New England Journal of Medicine,333:839–844 (1995). Sazawal evaluated the impact of zinc supplementation in a double blinded protocol involving 937 children, between the ages of 6 and 35 months. The authors reported that the group receiving zinc supplementation had a clinically significant reduction in both the duration and severity of diarrhea. Zinc supplementation was provided as part of a liquid daily multiple vitamin. All participants were allowed to consume ORS on a prn basis, if they had diarrhea.
A number of studies have been carried out evaluating the role of zinc in diarrhea. World Feeding Views, Volume 4, Number 1, (2000), at page 18, summarizes the results of 8 pediatric clinical studies involving zinc and diarrhea. Seven out of the eight studies report that zinc had beneficial effects on diarrhea. Various investigators observed a reduction in the duration of the diarrhea, a reduction in the number of watery stools, a reduction in stool output, and a reduction in the incidence. All participants were allowed to consume standard ORS solution as needed. Zinc supplementation was supplied separately from the ORS, typically as part of a vitamin regimen.
In view of the benefits which zinc supplementation has provided in the studies cited above, it would appear logical to incorporate zinc into ORS therapy. However, authors have expressed caution against such a strategy. Darmon et al discussed such a proposed ORS in journal of Pediatric Gastro-enterology and Nutrition 25: 363–365 (1997). Darmon et al, at page 364, 2nd column, points out that zinc inhibits the intestinal absorption of glucose. Since ORS therapy is based on an active transport mechanism, zinc might actually diminish the net absorption of sodium and water, leading to an ORS having decreased efficacy.
Another potential problem with zinc relates to its taste. The unpleasant taste of zinc is well documented in the literature regarding the use of zinc in treating the common cold. While zinc's impact on the common cold may be controversial, the negative metallic taste associated with zinc is not. For example, refer to Marshall's review of the use of zinc in Canadian Family Physician, 44:1037–1042 (1998.) Bad taste was a commonly observed complaint among participants.
Taste is an important factor in the rate of compliance with ORS, especially in children. The concentration of glucose in ORS is too low to mask the salty taste. Many children object to this taste and refuse to consume the ORS, even if the ORS is flavored. At the initiation of the research leading to this invention, the inventors believed that zinc would significantly decrease the palatability of the ORS and further exacerbate compliance issues, especially in a juvenile population.
The inventors belief is underscored by others knowledgeable in the field. U.S. Pat. No. 5,869,459, Waite et al, addresses the problem of pediatric compliance with ORS therapy. At column 3, line 8, Waite et al states that electrolytes generally have a disagreeable taste. The electrolytes create an unpleasant taste sensation, creating difficulties in getting young children to consume ORS's, despite their diarrhea.